Anlage Tumors of the Salivary Glands B4la Halpert, M. D., and Charles D. Tool, M. D.

(From the Department o[ Pathology of the School of Medicine of the University of Oklahoma, Oklahoma City 4, Oklahoma)

(Received for publication December 5, 1946)

Recently, Hellwig ( 11 ) reviewed the principal theories of the cellular origin of so-called salivary gland tmnors. He concluded that they are derived from misplaced elements of the notoehord. A group of salivary gland tumors was segregated by Stewart, Foote and Becket (18) and designated as "muco- epidermoid" tumors. For this type they implicated the salivary gland ducts as the anatomic site of origin. Another group was called "adenomyoepithelioma of the palatal mucous glands," by Bauer and Fox (3). These were believed to arise from the cells l ining the intercalated ducts of the palatal mucus glands.

Our inquiry into the structure of the so-called salivary gland tumors leads to the conclusion that they are derived from embryonal rcsts of the ecto- derm. The variations in cellular patterns suggest that the anlage separated at a stage when the cells as yet had not acquired their dominant characteris- tics as ectodermal or mesodermal cells. This explains their capacity to form ectodermal and mesodermal structures.

In this study only those growths believed to be benign and presenting the usual microscopic struc- ture of salivary gland tumors were included. The records and specimens of 38 patients with salivary gland tuinors observed during the past 15 years at the University of Oklahoma Hospitals were studied. T h e age, sex, and race of the patients, sites of the growths and their duration were also briefly con- sidered (Table I) .

Age, sex, and race.--Three of the patients were in the second, 4 in the third, 5 in thc fourth, 13 in the fifth, 7 in the sixth, 5 in the seventh and 1 in the eighth decade of life. The youngest patient was 14 and thc oldest 72 years of age. Nineteen patients were male and 19 wcre female. Four of thc patients were negro (2 male and 2 female).

Site and durat ion. - - In 29 patients, the growths occurred in or about the parotid glands (18 on the left and 11 on the right); in 6 patients, in or about the submandibular glands, (3 on the left and 3 on the right); and in 3 patients in the maxilla (right antrum, left hard palate and hard palate, respective-

rI 'ABLE I

PARDTID GLANDS

P a t i e n t ' s Sex a n d D u r a t i o n , Size n u m b e r Axe race Side years ('m.

P 1 1264 41 14 F \V L ; 4x4 P-2 1107-39 26 M N R 14 7xgx; P-3 1500 42 29 F \V R 8 3x3x2 P-4 178-37 30 F \V L 6 8x8 P-5 1715-37 31 F \V L 8 5x5 P6 1250-45 35 M\V R 19 5x5 P-7 859-45 38 F \V L 20 3x3 P-8 790-32 42 MXV L 9 raG. 2xlxl P-9 785-38 42 F \V R ~v 5xSx4 P-10 959-38 42 F N L 7 3x3 P-11 127-44 42 MXV R 4 6xSx3

) X 3 X , . , P-17 151-42 43 F W R 5 " P-13 1235-4l 44 M\V L 20 8x6 P-14 1690-37 47 MXV R 10 8x8 P-15 5-39 47 M\V L 27 5x5 P-16 462-46 48 M\V R 8 lx! 1;-17 1083-42 50 F \V R 18 5x6 P-18 1411-36 52 M\V L 17 3x3 P-19 480-40 54 F \V L 1 l 20xl ~x8

1302-40 5x5 P-20 2195-40 55 F \V L 4 2x2 P-21 883-43 56 F \V L 6 4x3 P-22 1264-46 56 F \V L 7 4x3x2 P-23 318-46 58 F N L 2 3x3x2 P-24 1333-38 64 MXV R 5 5x3x2 P-25 233-45 64 F \V L 3 3x3 P-26 205-41 67 F ~V L 16 8x8 P-27 1302-38 68 F XV R 1 3x2 P-28 713-37 70 MXV L 44 5x5 P-29 1158-38 72 MXV L 8 4x3x3

SUBMANDIBULAR GLANI)~

S 1 1891-41 28 M\V R 4 ;x4 S-2 1399-37 32 M\V L 9 3x2x2 $3 1032-38 42 F \V L 12 7x5 54 1060 37 43 F \V L 30 3x2 S~ 1841-41 50 F VV R 4 3x2 S-6 265-44 55 M\V R 3 raG. 5x4x2

~IAXILLA

M-1 144-45 15 M W Palate 3 mo. 2x2xl M-2 704-45 17 M N L palate 2 ),ears 7x5x2 M-3 1577-43 34 MW R antrum 1 mo. 5xlxl

ly). The time interval between the first appearance of the growth and its removal varied. The growths about the parotid and submandibular glands were

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Halpert and Tool--Tumors of Salivary Glands 347

removed within 1 year of their appearance in 3 pa- tients between 1 and 5 years in 9, between 5 and 10 years in 10, between 10 and 20 years in 9, and between 20 and 44 years in 4 of the patients. The growths in the maxilla, however, were removed much earlier, i. e., 1 month, 3 months and 2 years, respec- tively, after they were first noticed.

Structure.--Thc growths ranged between 1 and 20 cm. in diameter, but most of them were not over 6 cm. They were fairly firm, globular and frequently lobulated. Their cut surfaces varied and presented no uniform pattern. Occasional septa subdivided the gray white nodular fields. The growths were usu- ally surrounded by a more or less delicate capsule. However, occasionally no definite line of cleavage se- parated the growth from the surrounding structures. There was no fundamental difference in ~the gross appearance of the growths arising in the parotid re- gions and those situated elsewhere.

The microscopic appearance of the growths arising at any of the sites was closely similar, if not iden- tical. Neoplastic epithelial elements were enclosed within neoplastic connective tissue, both in varying degrees of differentiation. Frequently, an apparent transformation of epithelial elelncnts into connec- tive tissue elements could be observed.

In all growths, sheets of epithelial cells forming no particular patterns or structures were seen in nests or strands connected with one another (Fig. 1). Elsewhere, a stream-like or concentric arrange- ment of the epithelial cells was clearly discernible with intercellular bridges and occasional keratinized round masses forming epithelial pearls (Fig. 2). Lumina surrounded by epithelial cells resembling the structure of ducts of sweat glands were occa- sionally seen. Other lumina, small or large, were lined by cuboidal or colunmar cells with several rows of cell nuclei. In the larger cell nests pseudo- lumina, empty or containing a pink amorphous material, were seen singly or in varying numbers. A degree of differentiation to acinar tubular struc- tures lined by cuboidal or columnar cells, producing a mucinous or serous secretion, and arranged in a pattern forming glandular structures was only occa- sionally observed (Fig. 3).

The neoplastic connective tissue elements form- ing the stroma, like the epithelial elements, varied in the degree of their differentiation. There were fields of embryonal connective tissue composed of cells with stellate processes fading into a barely stainable ground substance (Fig. 4). There were other fields of young connective tissue producing collagen. Fields of adult connective tissue, of em- bryonal young or adult hyaline cartilage, and of

osteoid or osseous tissue were also seen. Quite fre- quently a barely percep,tible transformation of the pink-stained ground substance into cartilage could be observed (Figs. 1 and 2). Elsewhere epithelial cells were seen scattered in nests, or spread apart into single file and transformed into cells of the cartilage (Fig. 5). A mucin-like fibrillar ground substance with scattered groups of epithelial cells was observed in some of the growths, fading gradually into young hyaline cartilage (Fig. 6). In some instances, there were scattered groups of adipose tissue cells (Fig. 7). In an occasional growth, groups of round or oval empty spaces were seen lined by flat cells resembling endothelial cells. The lumina appeared in groups and seemed to connect with one another (Fig. 8). In other instances, obviously epithelial cells lined similar spaces communicating with one another (Fig. 9).

While the growths were usually delimited by a definite capsule, portions occasionally extended into the nearby glandular tissue without disturbing or distorting the pattern of the gland.

C O M M E N T

Benign growths composed of neoplastic epithelial and neoplastic connective tissue elements usually occur in, near or about the large salivary glands, and are therefore called mixed tumors of the salivary glands. They occur most commonly in or about the parotid glands (1, 6, 12-14, 16, 19), less fre- quently about the submandibular glands and rarely about the sublingual glands (17). They have also been observed occasionally near the root of the nose, (8), in the nasal septum (7), the palate (15), and pharynx (2), the tongue (5), and the lips (4, 10).

The sites of origin on the face usually correspond to or near lines of fwion of embryonal facial fissures. This circumstance and their structural patterns suggest that, like the adamantinomas and eraniopharyngiomas, they are derived from embry- onal rests of the ectoderm. The structural differ- ences between the adamantinomas and craniopharyn- giomas on the one hand, and the salivary gland tumors on the other, may be attributed to at least two factors. One of these is the influence of the environment on the neoplasms in their respective sites. The other factor is the stage of evolution of the cell rests at the time of separation from the ectodermal anlage.

Adamantinomas and craniopharyngiomas are evi- dently of more recent genetic origin, hence their simpler range of variation in cellular patterns. The stroma in these growths is a contribution of the

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348 Cancer P~esearch

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tlalpert and Tool--'l'umors of Salivary Glands 349

surrounding connective tissue, whereas in tumors of the salivary gland it is a part of the neoplasm (9).

The salivary gland tumors appear to be genetically the oldest of the three. The group of cells from which they are derived must have separated from the ectoderm at the stage when they had as yet not acquired the dominant characteristics as ecto- dermal or mesodennal cells; hence their capacity to differentiate into both ectodermal and meso- dermal tissues. This explains the variations in their individual structural patterns, namely, the presence in varying proportions of undifferentiated and diff- erentiated epithelial elements, of embryonal con- nective tissue, adipose tissue, endothelial-lined spaces, young and adult connective tissue, hyaline cartilage and osseous tissue. It also explains the apparent transformation of ectodermal elements into meso- dermal tissue elements, such as the gradual trans- ition of epithelial cells into cells of hyaline cartilage. It also explains the occasional extension of the growth into the nearby glandular tissue without disturbing or distorting the pattern of the gland.

SUMMARY

'l'he cellular structures of anlage tumors occur- ring in the salivary glands wcrc studied in 38 pa- tients. In 29, the growth occurred in or about the parotid glands; in 6, about the submandibular glands; and in 3, in the maxilla. There was no fundamental diffcrcnce in the gross appearance or microscopic structure of thc growths arising in the parotid regions and of those situated elsewhere.

The sites of origin and their structural patterns suggest that, like adamantinomas and craniopharyn- giomas, thcy arc derived from embryonal rcsts of

the ectoderm. The structural differences may bc attributed partly to influences of the environment on the tumors in their respective sites, and in part to the stage of evolution of the cell rests at the time of separation from the ectodermal anlagc.

The saliwlry gland tumors appear to be the oldest genetically. The group of cells from which they originate must have separated from the ectoderm at the stage when they had as yet not acquired their dominant characteristics as ectodermal and mcsodcrmal cclls; hcncc, thcir capacity to differen- tiate into ectodermal and mesodcrmal tissues. The adamantinonras and craniopharyngiomas are evident- ly of more recent genetic origin; hence, their simpler range of variation in cellular pattern. The stroma in these growths is a contribution of thc surrounding conncctive tissue, whereas in tumors of the salivary glands it is a part of the neoplasm.

R E F E R E N C E S

1. AULBOM, tt. E. Mucous- and Salivary-Gland Tu- rnouts. Clinical Study with Special il, eference to Radiotherapy, Based on 254 Cascs Treated at Ra- diumhemmet, Stockhohn. Acta. radiol., supp. 23: 1-452. 1935.

2. BATES, C. E. ti. Mixed Salivary Tumor in the Right Tonsil Fossa with Narcolepsy and Cataplexy. Ann. Otol. Rhin. & Laryng., 54:812 817. 1945.

3. BAttER, \V. H., and Fox, R. A. Adenomyocpithe- lioma (Cylindroma) of Palatal Mucous Glands. Arch. Path., :39:96-102. 1945.

q-. BERNIER, ]. L. Mixed Tumors of the Lip. ]. Oral Surg., 4:193 202. 1946.

~. Co~:sR, \V. G. Mixed Tumor of the Tongue. J. Bowman Gray School of Medicine, 4:49-55. 1946.

6. DOCKERTY, M. B., and X laYo, C. \V. Primary Tu- mors of the Submaxillary Gland with Special Refer- ence to Mixed Tumors. Surg., Gynec., & Obst., 74:1033-1045. 1942.

DESCI~,IPTION OF HGURES 1 TO 0

Fro. l.--Sheets of epithelial cells forming no particular pattern are seen in nests and strands in hyaline-like ground substance fading into cartilage. In the larger cell nests, there are various-sized lumina or pseudo-lmnina, mostly empty or containing pink amorphous material. (P-25) Mag. )< 110.

FIe. 2.--Sheets of epithelial cell~ form no particular pattern and are in nests, strands, or in stream-like con- centric arrangement with clearly discernible intercellular bridges and keratinized round masses forming epithelial pearls. (P-12) Mag. ;K 110.

Fro. 3--Acinar tubular structures are lined bv cuboidal or columnar cells producing a nmcinous secretion and are arranged in pattern forming glandular structures. (P-22) Mag. >< 110.

Fic. ar.--Fields of embryonal connective tissue com-

poscd of cells with stellate processes fade into barely stainable ground substance. (P-29) Mag. X 110.

Fro. 5.--Epithelial cells are scattered in nests or spread apart into single file and are transformed into cells of cartilage. (P-4) Mag. X 110.

Fro. 6.--A mucin-like fibrillar ground substance with scattered groups of epithelial cells fades gradually into young hyaline cartilage. (P-3) Mag. X It0.

Fro. 7.--Scattered groups of adipose tissue cells are seen in the loose connective tissue septa between epithelial cells. (P-2) Mag. X, l l0.

FIe. 8.--Groups of round or oval empty spaces are lined bv flat cells resembling endothelial cells. (P-6) Mag. X 110.

Fro. 9.--Lumina communicating with one another are lined by flat epithelial cells closely resembling endothelial lined spaces. (S-4) Mag. 5< 110.

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50 C a n c e r Resea rch

7. ERSNER, M. S., and SALTZ~,IAN, M. A Mixed Tmnor of the Nasal Septum. Report of a Case. Laryngo- scope, 54:287-296. 1944.

8. I IALF~RT, B. Salivary Gland Tumors in Rare Sites. Report of Two Cases. Yale J. Biol. & Med., 5: 469-471. 1933.

9. HALrrR'r, B. Salivary Gland Tumors, Adamantino- mas and Craniopharyngiomas. Anlage Tumors. Abstr., Proc. Am. Assoc. for Cancer Research, 1946. Cancer Research, 6:504. 1946.

10. HAZ~I]~ICI<, ~. G., and Itowv., ~. S. Mixed Tumor of the Lip. Report of Two Cases, Including One of Mixed Tumor of the Lower Lip. Arch. Path., 37. 143-146. 1944.

11. HELLWIC, C. A. Mixed Tumors of the Salivary Glands. Arch. Path, 40:1-10. 1945.

12. LEDERMAN, M. Mucous and Salivary Gland Tu- rnouts. Brit. ~. Radiol., 14:329-335: 1941.

13. MCFARLAND, J. Mysterious Mixed Tumors of the Salivary Glands. Surg., Gynec. & Obst., 76:23- 34. 1943.

14. ROBBINS, G. F. Tumors of Salivary Gland Origin. So-Called Mixed Tumors. Surgery, 14:924-930. 1943.

15. ROSY VALE, R. S. Mixed Tumors of the Palate. Ohio State M. J., 39:235-237. 1943.

16. SHELDON, W. It. So-Called Mixed Tumors of the Salivary Glands. Arch. Path., 35:1-20. 1943.

17. S~IITa, M. K. Mixed Tumors of the Sublingual Gland. Ann. Surg.. 109:551-554. 1939.

IS. STEWART, F. \V., FOOTF., F. "~V., and BECKER, \V. F. Muco-Epidermoid Tumors of Salivary Glands. Ann. Surg., 122:820-824. 1945.

19. SWqNTON, N. \V., and "vVARREN, S. Salivary Gland Tun-mrs. Surg,, Gynec. & Obst., 67:424-435. 1938.

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1947;7:346-350. Cancer Res   Béla Halpert and Charles D. Tool  Anlage Tumors of the Salivary Glands

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